The goal of this application is to support the development of Dr. Pradeep Singh as a clinician scientist so that at the completion of the award he will be an independent researcher and an outstanding academic scientist and clinician. Dr. Michael J. Welsh will assume responsibility as mentor to ensure the success of the development plan. The heart of the proposal is an intensive training experience in the basic research laboratory. Dr. Singh will study the defense mechanisms of human airway epithelia against bacterial infection. He will focus on the pathogenesis of colonization and infection in cystic fibrosis (CF). His proposed research has three specific aims. First, he will test the hypothesis that in the CF airway, the production or antimicrobial function of defensins is abnormal. These small antimicrobial peptides are likely important in protecting the airway from infection. Second, he will test the hypothesis that airway antimicrobial factors have activity against bacteria in biofilms or prevent their formation. In CF, the biofilm infection is very resistant to elimination. Third, he will test the hypothesis that the CF environment or epithelium predisposes to bacterial biofilm formation. This work will involve the development of an exciting new model to study pathogenesis. These basic studies will provide him with the training required to develop skills in molecular biology, cell biology, physiology, and microbiology. In addition, he will further develop his skills at using the scientific method to develop hypotheses that can be experimentally tested to yield unequivocal answers. In addition to basic research training, Dr. Singh will continue his training in biologic science with didactic courses, seminars and journal clubs. He will receive instructions in speaking and writing and will receive instruction in the responsible conduct of research. He will also attend national meetings to present his own work and to learn from others. Both the mentor and the institution are highly committed to the applicant's scientific development and academic success.